FXR调节胆汁酸合成和转运研究进展

374FXR周植星,王涛,江振洲,张陆勇*(,210009):法尼酯衍生物X受体;胆固醇7羟化酶;胆汁酸代谢;胆汁淤积:R963:B:16722981(2010)05037404X(farnesoidXreceptor,FXR),FXR,,FXR1,(CA)(CDCA)CYP7A1,CYP8B1,CYP27A1[1],CYP7A1CYP8B1FXRCYP27A1,,,,2524,7(CYP7B1),CDCA(BACS),(BAT),CACDCA,7,(DCA)(LCA)CACDCADCALCA,LCA(SULT2A1),[2],,,FXR,[3]FXR,FXR(RXR),FXR(AGGTCAnTGACCT,IR1),[4](CDCA)FXR,FXRX(PXR)D(VDR),2[5]CAMPC[6](TNF)1(IL1)(TNF)()(MAPK/JNK)[7]/3(PI3K)/(AKT)/3(GSK3)PI3KAKT,AKTGSK3GS3a/b/c,,[8]2FXRCYP7A1,,5CYP7A1[910]FXRCYP7A12FXRCYP7A1,FXR(SHP)CYP7A1,FXRCYP7A1,SHPSHP,DNA,,,DNASHP1(LRH1)CYP7A1,SHP4(HNF4)CYP7A1CYP8B1,LRH1:(:2007BAI30B04),(:2009ZX09302002):,,,,Tel:[phone],Email:zhouzhixing2004@sohucom*:,,,,Email:[e-mail]2010,Vol8No52010585375HNF4CYP7A1CYP8B1,LRH1HNF4CYP7A1CYP8B1[11]FXRFGF19FGF4(FGFR4)CYP7A1HoltFXRGW406419(FGF19)FXR,FGF194(FGFR4),CYP7A1[12],FXRFGF15(FGF19),FGF15mRNACYP7a1[13]FGFR4/FGF15/FGF15GW4064CYP7A1mRNA,FGF15/FGFR4CYP7A1,GW4064FXR,FXRCYP7A1CYP7A1FXR,FXR[14]FGF19FGF19FGF19,FXR/FGF19/FGFR43FXR31胆汁酸的肝肠循环,,,(BSEP)2(MRP2)3(MDR3),BSEP,MRP2,MDR3[15](),(ASBT),(IBABP),(tASBT),(NTCP)(OATP),NTCPOATP,BSEP,[3]95%,5%32FXR调节胆汁酸的转运体FXR,FXR[15]321FXRNTCP(NTCP),,,[16],FXRSHP,SHP,NTCP,FXR,FXR6FXRCDCA100,Zollner6,6FXRSHPNTCP[17],FXRSHPNTCP322FXRBSEP(BSEP),BSEPBSEPAnanthanarayananBSEPFXR(IR1),FXRBSEPFXR(/)BSEPBSEPFXR,BSEPFXR,CDCAGW4064,(LCA),FXR,BSEPLCACDCAGW4064FXR;LCAFXRBSEP,,[18]323FXRMRP2MRP2,,MRP2,MRP217(GSSG)[19]()MRP2,MRP2[20]MRP2MRP2(ICP)[21]Kast,FXRMRP2mRNAMRP2mRNAX(PXR)(CAR)[22],FXRMRP2BSEP,,()324FXRMDR33(MDR3)(ATPbindingcassette,ABC)MDR3ATP,,,2010585CentralSouthPharmacy.May2010,Vol8No5376,[23]MDR3FXRHuangMDR3mRNAFXRGW4064FXRMDR3,MDR3FXRMDR3[24],FXRBSEP,MDR3,325FXRIBABP(IBABP)14kD,,,IBABP,,IBABPFXRIBABP,FXR[25]IBABPFXRIR1,CDCAFXRIBABPIR1CDCAIBABP,FXRIBABP,[26]326FXROATP(OATP),,,[27]FXROATP,OATP,FXR(HNF)OATP,[28]Maeda,,FXR(/)OATP1OATP2OATP3,[29]FXROATP327FXR,(ASBT)ASBT,FXRASBT,ASBT,ASBT[30](OST),OST/OSTOST/OST,15(FGF15)CYP7A1[31],OST/OSTFXROSTFXR,FXROST/OST,FXROST/OST[3233]4,,FXR,6(PBC)FXR(BSEP)MRP2FXR[1]ChiangJY.Bileacids:regulationofsynthesis.[J]JLipidRes,2009,50(4):19551966.[2]HofmannAF.Detoxificationoflithocholicacid,atoxicbileacid:relevancetodrughepatotoxicity.[J]DrugMetabRev,2004,6(34):703722.[3]ChiangJY.BileAcidregulationofgeneexpression:rolesofnuclearhormonereceptors[J].EndocrRev,2002,23(4):443463.[4]FiorucciS,MencarelliA,PalladinoG,etal.Bileacidactivatedreceptors:targetingTGR5andfarnesoidXreceptorinlipidandglucosedisorders[J].TrendsPharmacolSci,2009,30(11):570580.[5]LinYS,YasudaK,AssemM,etal.ThemajorhumanpregnaneXreceptor(PXR)splicevariant,PXR.2,exhibitssignificantlydiminishedligandactivatedtranscriptionalregulation[J].DrugMetabDispos,2009,37(6):12951304.[6]NguyenA,BouscarelB.Bileacidsandsignaltransduction:roleinglucosehomeostasis[J].CellSignal,2008,20(12):21802197.[7]WatanabeM,HoutenSM,MatakiC,etal.Bileacidsinduceenergyexpenditurebypromotingintracellularthyroidhormoneactivation[J].Nature,2006,439(7075):484489.[8]FangY,StuderE,MitchellC,etal.ConjugatedbileacidsregulatehepatocyteglycogensynthaseactivityinvitroandinvivoviaGalphaisignaling[J].MolPharmacol,2007,71(4):11221128.[9]SongKH,EllisE,StromS,etal.Hepatocytegrowthfactorsignalingpathwayinhibitscholesterol7alphahydroxylaseandbileacidsynthesisinhumanhepatocytes[J].Hepatology,2007,46(6):19932002.[10]MitroN,GodioC,DeFabianiE,etal.Insightsintheregulationofcholesterol7alphahydroxylasegenerevealatargetformodulatingbileacidsynthesis[J].Hepatology,2007,46(3):885897.[11]LeeYK,SchmidtDR,CumminsCL,etal.Liverreceptorhomolog1regulatesbileacidhomeostasisbutisnotessentialforfeedbackregulationofbileacidsynthesis[J].MolEndocrinol,2008,22(6):13451356.[12]HoltJA,LuoG,BillinAN,etal.Definitionofanovelgrowthfactordependentsignalcascadeforthesuppressionofbileacidbiosynthesis.[J]GenesDev,2003,17(13):15811591.[13]InagakiT,ChoiM,MoschettaA,etal.Fibroblastgrowthfactor15functionsasanenterohepaticsignaltoregulatebileacidhomeostasis.[J]CellMetab,2005,2(4):217225.CentralSouthPharmacy.May2010,Vol8No52010585377[14]KimI,AhnSH,InagakiT,etal.DifferentialregulationofbileacidhomeostasisbythefarnesoidXreceptorinliverandintestine[J].JLipidRes,2007,48(12):26642672.[15]WagnerM,ZollnerG,TraunerM.Newmolecularinsightsintothemechanismsofcholestasis[J].JHepatol,2009,51(3):565580.[16]RizzoG,RengaB,MencarelliA,etal.RoleofFXRinregulatingbileacidhomeostasisandrelevanceforhumandiseases[J].CurrDrugTargetsImmuneEndocrMetabolDisord,2005,5(3):289303.[17]ZollnerG,WagnerM,FickertP,etal.RoleofnuclearreceptorsandhepatocyteenrichedtranscriptionfactorsforNtcprepressioninbiliaryobstructioninmouseliver[J].AmJPhysiolGastrointestLiverPhysio,2005,289(5):G798805.[18]AnanthanarayananM,BalasubramanianN,MakishimaM,etal.HumanbilesaltexportpumppromoteristransactivatedbythefarnesoidXreceptor/bileacidreceptor[J].JBiolChem,2001,276(31):2885728865.[19]BanD,KudoA,SuiS,etal.DecreasedMrp2dependentbileflowinthepostwarmischemicratliver[J].JSurgRes,2009,153(2):310316.[20]KandaD,TakagiH,KawaharaY,etal.Novellargescaledeletion(wholeexon7)intheABCC2genei